The objective of this proposal is to continue evaluation of the theory that deficiency in central neurotransmitters is related to the genesis and evolution of cognitive impairment in senile dementia. Specifically, we will evaluate further the hypothesis that deficiency in availability of brain acetylcholine (ACh) is related to senile dementia of the Alzheimer's type (SDAT). This will be done by studying the effects of agents which enhance cholinergic functioning. The rationale is based on evidence that the cholinergic system is directly involved in the memory process; that a selective loss of cholinergic neurons and of the ACh synthesizing enzyme, CAT, occurs in SDAT; and that administration of dietary choline or lecithin elevates brain levels and activity of ACh. A total of about 300 healthy outpatients (aged 60-85) with mild to moderate SDAT will be studied. In Project 1 we will conduct 5 parallel studies to evaluate the effects of single doses of the ACh precursor lecithin; the acetylcholinesterase inhibitor physostigmine; the muscarinic receptor agonist arecoline; lecithin plus physostigmine; and lecithin plus arecoline. 20 patients will be assigned to each study. A double-blind crossover design will be employed, with treatment days spaced 1 week apart. The optimal safe doses of these agents will be determined individually for each patient. The results will indicate which sites of action (presynpatic, synaptic or postsynaptic) can be successfully manipulated in SDAT, thereby suggesting the best treatment strategy. In Project 2, we will evaluate the hypothesis that long term (1 year) treatment with lecithin may serve to prevent further cognitive decline in SDAT. A total of 120 SDAT patients (and about 30 multi-infarct patients) will be evaluated in a double-blind, parallel groups design. Half will receive lecithin (3.0 g free choline-day) and half will receive placebo. Extensive cognitive, behavioral and medical-neurological evaluations will be employed to assess the potential prophylactic effects of dietary lecithin. If successful, the results will verify an important treatment strategy for preventing SDAT.